PROJECT SUMMARY This career development award will allow Dr. Torchen to develop the experience and skill set required to achieve her long term goal of establishing an independent research program primarily focused on investigation of the developmental and genetic origins of polycystic ovary syndrome (PCOS). Through this work, Dr. Torchen hopes to translate her research findings into clinical practice in order to improve early prevention and treatment interventions for this disorder. If these goals are achieved, she will have a lasting impact on her scientific field and improve the clinical care of patients with PCOS. Controversy regarding diagnosis of PCOS during early adolescence has delayed implementation of prevention and treatment strategies, so the impact of Dr. Torchen?s proposed work is significant. Dr. Torchen will use this award to enhance her skills in execution of physiologic protocols and to develop skills in statistical and molecular genetics. These skills will leave her well-positioned to successfully compete for independent funding in the next phase of her career. Dr. Torchen will achieve her training goals through a career development plan that consists of intensive mentorship, completion of a Master?s Degree of Science in Clinical Investigation, participation in institutional scientific and career development seminars, and attendance and presentation at national meetings. Her primary mentor is Dr. Andrea Dunaif, an expert in clinical studies in PCOS, who has ongoing NIH support and an excellent record of mentorship. Her secondary mentors are Dr. Robert Rosenfield, a pediatric endocrinologist and international expert in reproductive physiology in childhood and adolescence, and Dr. Margrit Urbanek, a molecular and statistical geneticist focused on identification of genes important in the pathogenesis of complex genetic traits. The overall goal of Dr. Torchen?s research strategy is to identify early clinical and genetic markers of PCOS in daughters of affected women and obese girls. Aim 1 will test the hypothesis that early adolescent postmenarchal PCOS daughters will have a distinct reproductive and metabolic phenotype characterized by ovarian hyperandrogenism, increased ovarian follicle count, and evidence for pancreatic ?-cell dysfunction, which hyperandrogenic obese girls and control girls will lack. Aim 2 will test the hypothesis that early adolescent PCOS daughters with ovarian hyperandrogenism and increased ovarian follicle count will fulfill diagnostic criteria for PCOS at postmenarchal age three years, while hyperandrogenic obese girls will fail to meet these criteria. Aim 3 will test the hypothesis that a PCOS genetic risk score will predict the diagnosis of PCOS in this adolescent cohort.